EEG spike source localization before and after surgery for temporal lobe epilepsy: a BOLD EEG-fMRI and independent component analysis study

Simultaneous measurements of EEG-functional magnetic resonance imaging (fMRI) combine the high temporal resolution of EEG with the distinctive spatial resolution of fMRI. The purpose of this EEG-fMRI study was to search for hemodynamic responses (blood oxygen level-dependent - BOLD responses) associated with interictal activity in a case of right mesial temporal lobe epilepsy before and after a successful selective amygdalohippocampectomy. Therefore, the study found the epileptogenic source by this noninvasive imaging technique and compared the results after removing the atrophied hippocampus. Additionally, the present study investigated the effectiveness of two different ways of localizing epileptiform spike sources, i.e., BOLD contrast and independent component analysis dipole model, by comparing their respective outcomes to the resected epileptogenic region. Our findings suggested a right hippocampus induction of the large interictal activity in the left hemisphere. Although almost a quarter of the dipoles were found near the right hippocampus region, dipole modeling resulted in a widespread distribution, making EEG analysis too weak to precisely determine by itself the source localization even by a sophisticated method of analysis such as independent component analysis. On the other hand, the combined EEG-fMRI technique made it possible to highlight the epileptogenic foci quite efficiently.58258

High-Throughput Proteomics Detection of Novel Splice Isoforms in Human Platelets

Alternative splicing (AS) is an intrinsic regulatory mechanism of all metazoans. Recent findings suggest that 100% of multiexonic human genes give rise to splice isoforms. AS can be specific to tissue type, environment or developmentally regulated. Splice variants have also been implicated in various diseases including cancer. Detection of these variants will enhance our understanding of the complexity of the human genome and provide disease-specific and prognostic biomarkers. We adopted a proteomics approach to identify exon skip events - the most common form of AS. We constructed a database harboring the peptide sequences derived from all hypothetical exon skip junctions in the human genome. Searching tandem mass spectrometry (MS/MS) data against the database allows the detection of exon skip events, directly at the protein level. Here we describe the application of this approach to human platelets, including the mRNA-based verification of novel splice isoforms of ITGA2, NPEPPS and FH. This methodology is applicable to all new or existing MS/MS datasets

EEG spike source localization before and after surgery for temporal lobe epilepsy: a BOLD EEG-fMRI and independent component analysis study

Simultaneous measurements of EEG-functional magnetic resonance imaging (fMRI) combine the high temporal resolution of EEG with the distinctive spatial resolution of fMRI. The purpose of this EEG-fMRI study was to search for hemodynamic responses (blood oxygen level-dependent - BOLD responses) associated with interictal activity in a case of right mesial temporal lobe epilepsy before and after a successful selective amygdalohippocampectomy. Therefore, the study found the epileptogenic source by this noninvasive imaging technique and compared the results after removing the atrophied hippocampus. Additionally, the present study investigated the effectiveness of two different ways of localizing epileptiform spike sources, i.e., BOLD contrast and independent component analysis dipole model, by comparing their respective outcomes to the resected epileptogenic region. Our findings suggested a right hippocampus induction of the large interictal activity in the left hemisphere. Although almost a quarter of the dipoles were found near the right hippocampus region, dipole modeling resulted in a widespread distribution, making EEG analysis too weak to precisely determine by itself the source localization even by a sophisticated method of analysis such as independent component analysis. On the other hand, the combined EEG-fMRI technique made it possible to highlight the epileptogenic foci quite efficiently

Eeg Spike Source Localization Before And After Surgery For Temporal Lobe Epilepsy: A Bold Eeg-fmri And Independentcomponent Analysis Study

Simultaneous measurements of EEG-functional magnetic resonance imaging (fMRI) combine the high temporal resolution of EEG with the distinctive spatial resolution of fMRI. The purpose of this EEG-fMRI study was to search for hemodynamic responses (blood oxygen level-dependent - BOLD responses) associated with interictal activity in a case of right mesial temporal lobe epilepsy before and after a successful selective amygdalohippocampectomy. Therefore, the study found the epileptogenic source by this noninvasive imaging technique and compared the results after removing the atrophied hippocampus. Additionally, the present study investigated the effectiveness of two different ways of localizing epileptiform spike sources, i.e., BOLD contrast and independent component analysis dipole model, by comparing their respective outcomes to the resected epileptogenic region. Our findings suggested a right hippocampus induction of the large interictal activity in the left hemisphere. Although almost a quarter of the dipoles were found near the right hippocampus region, dipole modeling resulted in a widespread distribution, making EEG analysis too weak to precisely determine by itself the source localization even by a sophisticated method of analysis such as independent component analysis. On the other hand, the combined EEG-fMRI technique made it possible to highlight the epileptogenic foci quite efficiently.426582587Engel Jr., J., Introduction to temporal lobe epilepsy (1996) Epilepsy Res, 26, pp. 141-150Ives, J.R., Warach, S., Schmitt, F., Edelman, R.R., Schomer, D.L., Monitoring the patient's EEG during echo planar MRI (1993) Electroencephalogr Clin Neurophysiol, 87, pp. 417-420Allen, P.J., Josephs, O., Turner, R., A method for removing imaging artifact from continuous EEG recorded during functional MRI (2000) Neuroimage, 12, pp. 230-239Ritter, P., Villringer, A., Simultaneous EEG-fMRI (2006) Neurosci Biobehav Rev, 30, pp. 823-838Zijlmans, M., Huiskamp, G., Hersevoort, M., Seppenwoolde, J.H., van Huffelen, A.C., Leijten, F.S., EEG-fMRI in the preoperative work-up for epilepsy surgery (2007) Brain, 130, pp. 2343-2353Lemieux, L., Krakow, K., Fish, D.R., Comparison of spike-triggered functional MRI BOLD activation and EEG dipole model localization (2001) Neuroimage, 14, pp. 1097-1104Bagshaw, A.P., Kobayashi, E., Dubeau, F., Pike, G.B., Gotman, J., Correspondence between EEG-fMRI and EEG dipole localisation of interictal discharges in focal epilepsy (2006) Neuroimage, 30, pp. 417-425Belliveau, J.W., Rosen, B.R., Kantor, H.L., Rzedzian, R.R., Kennedy, D.N., McKinstry, R.C., Functional cerebral imaging by susceptibility-contrast NMR (1990) Magn Reson Med, 14, pp. 538-546Ogawa, S., Lee, T.M., Kay, A.R., Tank, D.W., Brain magnetic resonance imaging with contrast dependent on blood oxygenation (1990) Proc Natl Acad Sci U S A, 87, pp. 9868-9872Delorme, A., Makeig, S., EEGLAB: An open source toolbox for analysis of single-trial EEG dynamics including independent component analysis (2004) J Neurosci Methods, 134, pp. 9-21Plummer, C., Harvey, A.S., Cook, M., EEG source localization in focal epilepsy: Where are we now? (2008) Epilepsia, 49, pp. 201-218Leal, A.J., Dias, A.I., Vieira, J.P., Analysis of the EEG dynamics of epileptic activity in gelastic seizures using decomposition in independent components (2006) Clin Neurophysiol, 117, pp. 1595-1601Kobayashi, E., Bagshaw, A.P., Benar, C.G., Aghakhani, Y., Andermann, F., Dubeau, F., Temporal and extratemporal BOLD responses to temporal lobe interictal spikes (2006) Epilepsia, 47, pp. 343-354Mintzer, S., Cendes, F., Soss, J., Andermann, F., Engel Jr, J., Dubeau, F., Unilateral hippocampal sclerosis with contralateral temporal scalp ictal onset (2004) Epilepsia, 45, pp. 792-80

The Impact Of The Search For Thrombophilia Risk Factors Among Antiphospholipid Syndrome Patients With Thrombosis.

Thrombosis is a major clinical feature of the antiphospholipid syndrome. Interactions between genetic and acquired factors could contribute to thrombosis development. In this study, we evaluated 40 patients with antiphospholipid syndrome and thrombosis, 31 primary and nine secondary to systemic lupus erythemathosus, to estimate the carrier rates of factor V Leiden, 20210A --> G prothrombin variant and 677C --> T in the MTHFR gene. Protein C, protein S and antithrombin were measured in 30 patients, with a median of 100.66 +/- 23.86, 93.57 +/- 36.44 and 98.8 +/- 5.67%, respectively. None of the patients were deficient on these natural anticoagulants. No significant variation was found between the patient group and the controls, regarding the prevalence of homozygotes for the mutated 677T allele (2.5 versus 5.4%), or heterozygotes for factor V Leiden (0 versus 0.7%). Despite the fact that these mutations are relatively common in Brazilian thrombophilic patients, its low prevalence in this cohort of patients suggest that these genetic alterations are not risk factors for thrombosis in antiphospholipid syndrome. The prevalence of the mutated allele 20210A of the prothrombin gene was higher in patients when compared with controls (5 versus 0.7%; P = 0.01), suggesting that prothrombin variant could increase the risk of thrombosis in patients with antiphospholipid syndrome.11679-8

A longitudinal evaluation of anti‐FVIII antibodies demonstrated IgG4 subclass is mainly correlated with high‐titre inhibitor in haemophilia a patients

The development of inhibitory antibodies against factor VIII (FVIII) (inhibitor) is the major complication in haemophilia A patients. The FVIII‐binding antibodies development comprises a polyclonal immunoglobulin (Ig) G response. Recent studies showed strong correlation between the presence of neutralizing anti‐FVIII antibodies (inhibitors) and IgG4 subclass. The aim of this study was to evaluate anti‐FVIII IgG subclasses in haemophilia A patients with inhibitor both in a cross‐sectional and in a longitudinal analysis. Inhibitors were determined by Nijmegen–Bethesda assay. Anti‐FVIII IgG subclasses were performed by ELISA, and samples from 20 healthy individuals were used to validate the test. We studied 25 haemophilia A patients with inhibitor, previously treated exclusively with plasma‐derived FVIII concentrates or bypassing agents. The IgG subclasses distributions were evaluated in two groups of patients classified according to inhibitor response. IgG1 and IgG4 antibodies were most prominent in haemophilia A patients with inhibitors when compared with IgG2 and IgG3. This study reports for the first time the behaviour of FVIII‐binding IgG1 and IgG4 subclasses in a longitudinal analysis, in a clinical setting, of high‐response inhibitor haemophilia A patients, showing the correlation of IgG4 and the inhibitor titres. In spite of being considered a non‐pathologic antibody subclass with anti‐inflammatory properties in other situations, IgG4 is correlated with the presence of high‐titre inhibitor in the haemophilia setting. The comprehension of the IgG4 role in immune response may be crucial to establish the process for designing specific tolerance to FVIII21568669

Allergic Reaction In A Cohort Of Haemophilia A Patients Using Plasma-derived Factor Viii (fviii) Concentrate Is Rare And Not Necessarily Triggered By Fviii.

In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma-derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti-FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti-pdFVIII IgE and IgG4, but no anti-recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high-responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti-pdFVIII and anti-rFVIII IgG4 were detected, no anti-FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti-FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti-FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII.21e281-28

A Longitudinal Evaluation Of Anti-fviii Antibodies Demonstrated Igg4 Subclass Is Mainly Correlated With High-titre Inhibitor In Haemophilia A Patients.

The development of inhibitory antibodies against factor VIII (FVIII) (inhibitor) is the major complication in haemophilia A patients. The FVIII-binding antibodies development comprises a polyclonal immunoglobulin (Ig) G response. Recent studies showed strong correlation between the presence of neutralizing anti-FVIII antibodies (inhibitors) and IgG4 subclass. The aim of this study was to evaluate anti-FVIII IgG subclasses in haemophilia A patients with inhibitor both in a cross-sectional and in a longitudinal analysis. Inhibitors were determined by Nijmegen-Bethesda assay. Anti-FVIII IgG subclasses were performed by ELISA, and samples from 20 healthy individuals were used to validate the test. We studied 25 haemophilia A patients with inhibitor, previously treated exclusively with plasma-derived FVIII concentrates or bypassing agents. The IgG subclasses distributions were evaluated in two groups of patients classified according to inhibitor response. IgG1 and IgG4 antibodies were most prominent in haemophilia A patients with inhibitors when compared with IgG2 and IgG3. This study reports for the first time the behaviour of FVIII-binding IgG1 and IgG4 subclasses in a longitudinal analysis, in a clinical setting, of high-response inhibitor haemophilia A patients, showing the correlation of IgG4 and the inhibitor titres. In spite of being considered a non-pathologic antibody subclass with anti-inflammatory properties in other situations, IgG4 is correlated with the presence of high-titre inhibitor in the haemophilia setting. The comprehension of the IgG4 role in immune response may be crucial to establish the process for designing specific tolerance to FVIII

Frequency Of Platelet Type Versus Type 2b Von Willebrand Disease: An International Registry-based Study

Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses. © Schattauer 2011.1053501508Sadler, J.E., Rodeghiero, F., Provisional criteria for the diagnosis of VWD type 1 (2005) Journal of Thrombosis and Haemostasis, 3 (4), pp. 775-777. , DOI 10.1111/j.1538-7836.2005.01245.xTitani, K., Kumar, S., Takio, K., Amino acid sequence of human von Willebrand factor (1986) Biochemistry, 25 (11), pp. 3171-3184Mancuso, D.J., Tuley, E.A., Westfield, L.A., Worrall, N.K., Shelton-Inloes, B.B., Sorace, J.M., Alevy, Y.G., Sadler, J.E., Structure of the gene for human von Willebrand factor (1989) Journal of Biological Chemistry, 264 (33), pp. 19514-19527Federici, A.B., Mannucci, P.M., Stabile, F., Canciani, M.T., Di, R.N., Miyata, S., Ware, J., Ruggeri, Z.M., A type 2b von Willebrand disease mutation (lle 546 &gtVal) associated with an unusual phenotype (1997) Thrombosis and Haemostasis, 78 (3), pp. 1132-1137Casonato, A., Sartorello, F., Pontara, E., Gallinaro, L., Bertomoro, A., Cattini, M.G., Daidone, V., Pagnan, A., A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: An elusive phenotype and a difficult diagnosis (2007) Thrombosis and Haemostasis, 98 (6), pp. 1182-1187. , DOI 10.1160/TH07-05-0347Baronciani, L., Federici, A.B., Beretta, M., Cozzi, G., Canciani, M.T., Mannucci, P.M., Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding (2005) Journal of Thrombosis and Haemostasis, 3 (12), pp. 2689-2694. , DOI 10.1111/j.1538-7836.2005.01638.xTakimoto, Y., Imanaka, F., Type 2B Hiroshima: A variant of von Willebrand disease characterized by chronic thrombocytopenia and the presence of all von Willebrand factor multimers in plasma (1999) Int J Hematol, 70, pp. 127-131Poon, M.C., Rand, M.L., Jackson, S.C., 2B or not to be - The 45-year saga of the Montreal Platelet Syndrome (2010) Thromb Haemost, 104, pp. 903-910Weiss, H.J., Meyer, D., Rabinowitz, R., Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers (1982) New England Journal of Medicine, 306 (6), pp. 326-333Miller, J.L., Castella, A., Platelet-type von Willebrand's diseaseCharacterization of a new bleeding disorder (1982) Blood, 60 (3), pp. 790-794Miller, J.L., Platelet-type von Willebrand disease (1996) Thrombosis and Haemostasis, 75 (6), pp. 865-869Favaloro, E.J., Bonar, R., Meiring, M., Street, A., Marsden, K., 2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD (2007) Thrombosis and Haemostasis, 98 (2), pp. 346-358. , DOI 10.1160/TH06-12-0693Whalley, I.N., Perry, D.J., 2B or not 2B? Differential identification of Type 2B, versus pseudo-,von Willebrand disease (2007) Br J Haematol, 136, p. 345. , author reply -346Othman, M., Lillicrap, D., Distinguishing between non-identical twins: Platelet type and type 2B von Willebrand disease [2] (2007) British Journal of Haematology, 138 (5), pp. 665-666. , DOI 10.1111/j.1365-2141.2007.06690.xEnayat, M.S., Guilliatt, A.M., Lester, W., Wilde, J.T., Williams, M.D., Hill, F.G.H., Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importance (2006) British Journal of Haematology, 133 (6), pp. 664-666. , DOI 10.1111/j.1365-2141.2006.06078.xMathew, P., Greist, A., Maahs, J.A., Lichtenberg, E.C., Shapiro, A.D., Type 2B vWD: The varied clinical manifestations in two kindreds (2003) Haemophilia, 9 (1), pp. 137-144Saba, H.I., Saba, S.R., Dent, J., Type IIB tampa: A variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation (1985) Blood, 66 (2), pp. 282-286Olson, J.D., Preston, F.E., Nichols, W.L., External quality assurance in thrombosis and hemostasis: An international perspective (2007) Seminars in Thrombosis and Hemostasis, 33 (3), pp. 220-225. , DOI 10.1055/s-2007-971207Othman, M.L.J., Notley, C., James, P., Platelet Type von Willebrand disease: An under diagnosed cause of excessive mucocutanous bleeding (2007) J Thromb Haemost, 5 (SUPPL. 1). , Abstract P-W-167Othman, M., Ozelo, M., Brown, H., Canadian Platelet-type von Willebrand disease (PT-VWD) project: Progress and update (2009) J Thromb Haemost, 7 (SUPPL. 2). , Abstract OC-WE-134Othman, M., Hamilton, A., Platelet-type von Willebrand disease: Results of a worldwide survey from the Canadian PT-VWD project (2010) Acta Haematol, 123, pp. 126-128James, P.D., Notley, C., Hegadorn, C., Leggo, J., Tuttle, A., Tinlin, S., Brown, C., Lillicrap, D., The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study (2007) Blood, 109 (1), pp. 145-154. , http://www.bloodjournal.org/cgi/reprint/109/1/145, DOI 10.1182/blood-2006-05-021105Othman, M., Notley, C., Lavender, F.L., White, H., Byrne, C.D., Lillicrap, D., O'Shaughnessy, D.F., Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease (2005) Blood, 105 (11), pp. 4330-4336. , DOI 10.1182/blood-2002-09-2942Favaloro, E.J., 2B or not 2B? Differential identification of type 2B, versus pseudovon Willebrand disease (2006) Br J Haematol, 135, pp. 141-142. , author reply -143Favaloro, E.J., Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: A question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin? (2008) Semin Thromb Hemost, 34, pp. 113-127Frontroth, J.P., Hepner, M., Sciuccati, G., Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children (2010) Thromb Haemost, 104, pp. 1158-1165Favaloro, E.J., Patterson, D., Denholm, A., Mead, S., Gilbert, A., Collins, A., Estell, J., Smith, M.P., Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis [3] (2007) British Journal of Haematology, 139 (4), pp. 623-626. , DOI 10.1111/j.1365-2141.2007.06850.xScepansky, E., Othman, M., Smith, H., Acquired von Willebrand syndrome with a type 2B phenotype: Diagnostic and therapeutic dilemmas (2009) J Thromb Haemost, 5 (SUPPL. 1). , Abstract PP-MO-632Chegeni, R., Vickars, L., Favaloro, E.J., Functional analysis of three recombinant A1 -VWF domain mutants in comparison to wild type and plasma-derived VWF facilitates subtyping in type 2 von Willebrand disease (2010) Thromb Res, , published onlineOthman, M., Differential identification of PT-VWD from type 2B VWD and GP1BA nomenclature issues (2008) Br J Haematol, 142, pp. 312-314. , author reply 314-315Facey, D.A., Favaloro, E.J., Maxwell, E., Baker, R., Hertzberg, M., Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families: Phenotype and genotype correlations (2000) American Journal of Hematology, 63 (4), pp. 197-199. , DOI 10.1002/(SICI)1096-8652(200004)63:43.0.CO;2-2Favaloro, E.J., Koutts, J., Brighton, T., Genetic testing for the diagnosis of von Willebrand Disease: Benefits and limitations (2010) J Coagul Dis, 2, pp. 37-47Corrales, I., Ramirez, L., Altisent, C., Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene (2009) Thromb Haemost, 101, pp. 570-576James, P., Lillicrap, D., The role of molecular genetics in diagnosing von Willebrand disease (2008) Semin Thromb Hemost, 34, pp. 502-508Othman, M., Favaloro, E.J., Genetics of type 2B von Willebrand disease: "true 2B", "tricky 2B", or "not 2B". What are the modifiers of the phenotype? (2008) Semin Thromb Hemost, 34, pp. 520-531Federici, A.B., Mannucci, P.M., Castaman, G., Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: A cohort study of 67 patients (2009) Blood, 113, pp. 526-534Lopez-Fernandez, M.F., Lopez-Berges, C., Martin-Bernal, J.A., Type IIB von Willebrand's disease associated with a complex thrombocytopenic thrombocytopathy (1988) Am J Hematol, 27, pp. 291-298Nurden, P., Debili, N., Vainchenker, W., Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia (2006) Blood, 108, pp. 2587-2595Nurden, P., Chretien, F., Poujol, C., Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease (2000) Br J Haematol, 110, pp. 704-714Nurden, A.T., Federici, A.B., Nurden, P., Altered megakaryocytopoiesis in von Willebrand type 2B disease (2009) J Thromb Haemost, 7 (SUPPL. 1), pp. 277-281Nurden, P., Gobbi, G., Nurden, A., Abnormal VWF modifies megakaryocytopoiesis: Studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B (2010) Blood, 115, pp. 2649-2656Ragni, M.V., Bontempo, F.A., Cortese, H.A., Von Willebrand disease and bleeding in women (1999) Haemophilia, 5 (5), pp. 313-317. , DOI 10.1046/j.1365-2516.1999.00342.xNovelli, E.M., Ragni, M.V., Genetics of bleeding disorders in women (2008) Semin Thromb Hemost, 34, pp. 509-51